High Melphalan Exposure Increases the Risk of Graft-versus-Host Disease in Pediatric Patients Undergoing Alpha-Beta T-Cell Depleted Haploidentical Transplantation

In a recent study, researchers from the University of California, San Francisco, have demonstrated that high exposure to melphalan significantly increases the risk of graft-versus-host disease (GVHD) and engraftment syndrome (ES) in pediatric patients undergoing alpha-beta T-cell depleted haploidentical hematopoietic cell transplantation (HCT). In their retrospective analysis of 85 pediatric patients, higher pharmacokinetically predicted melphalan exposure (>6.8 mg·hr/L) was strongly associated with elevated incidences of grades II-IV acute GVHD (39.3% vs. 10.1%, p=0.002) and grades III-IV acute GVHD (31.5% vs. 2.5%, p<0.001), compared to patients with lower exposure. Additionally, high melphalan exposure was linked to a significantly higher incidence of ES (48.8% vs. 19.1%, p=0.005).

Melphalan-based conditioning regimens have been commonly used in pediatric haploidentical HCT due to their relatively lower organ toxicity compared to busulfan or total-body irradiation. However, melphalan dosing based solely on body surface area (BSA) often results in inconsistent drug exposures, potentially increasing mucosal injury and subsequent GVHD risk. To address this issue, the researchers utilized a pharmacokinetic (PK) model to predict melphalan exposure based on individual patient characteristics, including age, obesity, and renal function. Patients were stratified into high and low exposure groups based on the median melphalan exposure value to assess the impact on transplantation outcomes.

The study demonstrated that high melphalan exposure was not only associated with increased acute GVHD but also chronic GVHD (27.2% vs. 7.4%, p=0.03), though it had no significant impact on non-relapse mortality (NRM) or relapse rates. However, graft-versus-host disease-free, relapse-free survival (GRFS) was significantly worse in the high-exposure group (46.4% vs. 64.6%, p=0.02). These findings indicate the necessity of individualized dosing strategies to optimize melphalan exposure, suggesting that precise, model-based dosing could mitigate GVHD risks and enhance overall transplant outcomes in pediatric patients undergoing alpha-beta T-cell depleted haploidentical transplantation.

Reference:
Dvorak CC, Cho S, Salinas Cisneros G, et al. High Melphalan Exposure Increases the Risk of Graft-versus-Host Disease in Pediatric Patients Undergoing Alpha-Beta T-Cell Depleted Haploidentical Transplantation. Transplantation and Cellular Therapy. 2025. https://doi.org/10.1016/j.jtct.2025.03.020